Growing evidence strongly suggests a correlation between prenatal inflammation and autism; yet the mecha- nisms that underlie this correlation are largely unknown. The pathophysiology of autism is proposed to arise from defects in neuronal circuitry. Animal models of prenatal exposure to maternal immune activation (MIA) demon- strate that the offspring exhibit abnormal behaviors reminiscent of autistic human behaviors. The increase in autism-like behaviors in MIA animal models is mediated by the pro-inflammatory cytokine IL-17A. IL-17A is pro- duced by CD4+T cells (TH17 cells) and activates the NF-?B signaling pathway in vitro. Resveratrol is a plant derived polyphenolic compound that suppresses IL-17A and has both anti-inflammatory and neuroprotective properties6-8. Interestingly, resveratrol has been shown to ameliorate autistic-like behaviors in a rodent model of ASD. Despite the available data on the role of inflammation in ASD etiology, there is a significant gap in knowledge regarding how inflammation affects the development of human neuronal circuitry. Here we will test the hypothesis that increased levels of IL-17A will impair the development of neuronal connectivity and that resveratrol can serve as a therapeutic modality through inhibition of IL-17A downstream signaling. The rationale for the proposed studies is that, determining the contribution of the different components of the Central Nervous system (CNS) and immune system will allow us to dissect the cellular mechanisms that underlie the role of neuronal inflammation in ASD pathology. The long-term goal of this project is to uncover the mecha- nisms underlying the pathology of autism associated with defects in neuronal connectivity that are induced by prenatal inflammation. The objectives of this application are: 1) to develop stem cell derived neural models and determine the effect of pro-inflammatory cytokines during neuronal development in vitro (Aim-1); 2) to investigate potential chromatin regulatory pathways that might underlie the effect of inflammation during neuronal develop- ment in vivo and in vitro (Aims 2-3); 3) to ascertain the therapeutic potential of plant supplements (i.e. resveratrol) in the pathology of autism (Aim1, 2 & 3). To address the objectives of this application, a combination of state of the art approaches including stem cell based and mouse models, imaging, transcriptome, epigenetic and bio- chemical technologies will be used. We expect that the objectives proposed in this application will provide: 1) clear mechanistic information on how neuronal inflammation might disrupt the normal development of human neuronal circuitry; 2) a testable pre-clinical model for dietary supplements such as resveratrol in the treatment of autism.
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